The present invention is directed to hydroxyeicosatetraenoic acid related compounds, compositions and methods of use. The compounds are particularly useful in treating dry eye.
Dry eye, also known generically as keratoconjunctivitis sicca, is a common ophthalmological disorder affecting millions of Americans each year. The condition is particularly widespread among post-menopausal women due to hormonal changes following the cessation of fertility. Dry eye may afflict an individual with varying severity. In mild cases, a patient may experience burning, a feeling of dryness, and persistent irritation such as is often caused by small bodies lodging between the eye lid and the eye surface. In severe cases, vision may be substantially impaired. Other diseases, such as Sjogren""s disease and cicatricial pemphigoid manifest dry eye complications.
Although it appears that dry eye may result from a number of unrelated pathogenic causes, all presentations of the complication share a common effect, that is the breakdown of the pre-ocular tear film, which results in dehydration of the exposed outer surface and many of the symptoms outlined above (Lemp, Report of the National Eye Institute/Industry Workshop on Clinical Trials in Dry Eyes, The CLAO Journal, volume 21, number 4, pages 221-231 (1995)).
Practitioners have taken several approaches to the treatment of dry eye. One common approach has been to supplement and stabilize the ocular tear film using so-called artificial tears instilled throughout the day. Other approaches include the use of ocular inserts that provide a tear substitute or stimulation of endogenous tear production.
Examples of the tear substitution approach include the use of buffered, isotonic saline solutions, aqueous solutions containing water soluble polymers that render the solutions more viscous and thus less easily shed by the eye. Tear reconstitution is also attempted by providing one or more components of the tear film such as phospholipids and oils. Phospholipid compositions have been shown to be useful in treating dry eye; see, e.g., McCulley and Shine, Tear film structure and dry eye, Contactologia, volume 20(4), pages 145-49 (1998); and Shine and McCulley, Keratoconjunctivitis sicca associated with meibomian secretion polar lipid abnormality, Archives of Ophthalmology, volume 116(7), pages 849-52 (1998). Examples of phospholipid compositions for the treatment of dry eye are disclosed in U.S. Pat. No. 4,131,651 (Shah et al.), U.S. Pat. No. 4,370,325 (Packman), U.S. Pat. No. 4,409,205 (Shively), U.S. Pat. No. 4,744,980 and U.S. Pat. No. 4,883,658 (Holly), U.S. Pat. No. 4,914,088 (Glonek), U.S. Pat. No. 5,075,104 (Gressel et al.), U.S. Pat. No. 5,278,151 (Korb et al.), U.S. Pat. No. 5,294,607 (Glonek et al.), U.S. Pat. No. 5,371,108 (Korb et al.), U.S. Pat. No. 5,578,586 (Glonek et al.). U.S. Pat. No. 5,174,988 (Mautone et al.) discloses phospholipid drug delivery systems involving phospholipids, propellants and an active substance.
U.S. Pat. No. 3,991,759 (Urquhart) discloses the use of ocular inserts in the treatment of dry eye. Other semi-solid therapy has included the administration of carrageenans (U.S. Pat. No. 5,403,841, Lang) which gel upon contact with naturally occurring tear film.
Another approach involves the provision of lubricating substances in lieu of artificial tears. For example, U.S. Pat. No. 4,818,537 (Guo) discloses the use of a lubricating, liposome-based composition, and U.S. Pat. No. 5,800,807 (Hu et al.) discloses compositions containing glycerin and propylene glycol for treating dry eye.
Aside from the above efforts, which are directed primarily to the alleviation of symptoms associated with dry eye, methods and compositions directed to treatment of the dry eye condition have also been pursued. For example, U.S. Pat. No. 5,041,434 (Lubkin) discloses the use of sex steroids, such as conjugated estrogens, to treat dry eye condition in post-menopausal women; U.S. Pat. No. 5,290,572 (MacKeen) discloses the use of finely divided calcium ion compositions to stimulate pre-ocular tear film production; and U.S. Pat. No. 4,966,773 (Gressel et al.) discloses the use of microfine particles of one or more retinoids for ocular tissue normalization.
Although these approaches have met with some success, problems in the treatment of dry eye nevertheless remain. The use of tear substitutes, while temporarily effective, generally requires repeated application over the course of a patient""s waking hours. It is not uncommon for a patient to have to apply artificial tear solution ten to twenty times over the course of the day. Such an undertaking is not only cumbersome and time consuming, but is also potentially very expensive. Transient symptoms of dry eye associated with refractive surgery have been reported to last in some cases from six weeks to six months or more following surgery.
The use of ocular inserts is also problematic. Aside from cost, they are often unwieldy and uncomfortable. Further, as foreign bodies introduced in the eye, they can be a source of contamination leading to infections. In situations where the insert does not itself produce and deliver a tear film, artificial tears must still be delivered on a regular and frequent basis.
Mucins are proteins which are heavily glycosylated with glucosamine-based moieties. Mucins provide protective and lubricating effects to epithelial cells, especially those of mucosal membranes. Mucins have been shown to be secreted by vesicles and discharged on the surface of the conjunctival epithelium of human eyes (Greiner et al., Mucous Secretory Vesicles in Conjunctival Epithelial Cells of Wearers of Contact Lenses, Archives of Ophthalmology, volume 98, pages 1843-1846 (1980); and Dilly et al., Surface Changes in the Anaesthetic Conjunctiva in Man, with Special Reference to the Production of Mucous from a Non-Goblet-Cell Source, British Journal of Ophthalmology, volume 65, pages 833-842 (1981)). A number of human-derived mucins which reside in the apical and subapical corneal epithelium have been discovered and cloned (Watanabe et al., Human Corneal and Conjunctival Epithelia Produce a Mucin-Like Glycoprotein for the Apical Surface, Investigative Ophthalmology and Visual Science, volume 36, number 2, pages 337-344 (1995)). Recently, Watanabe discovered a new mucin which is secreted via the cornea apical and subapical cells as well as the conjunctival epithelium of the human eye (Watanabe et al., IOVS, volume 36, number 2, pages 337-344 (1995)). These mucins provide lubrication, and additionally attract and hold moisture and sebaceous material for lubrication and the corneal refraction of light.
Mucins are also produced and secreted in other parts of the body including lung airway passages, and more specifically from goblet cells interspersed among tracheal/bronchial epithelial cells. Certain arachidonic acid metabolites have been shown to stimulate mucin production in these cells. Yanni reported the increased secretion of mucosal glycoproteins in rat lung by hydroxyeicosatetraenoic acid (xe2x80x9cHETExe2x80x9d) derivatives (Yanni et al, Effect of Intravenously Administered Lipoxygenase Metabolites on Rat Trachael Mucous Gel Layer Thickness, International Archives of Allergy And Applied Immunology, volume 90, pages 307-309 (1989)). Similarly, Marom has reported the production of mucosal glycoproteins in human lung by HETE derivatives (Marom et al., Human Airway Monohydroxy- eicosatetraenoic Acid Generation and Mucous Release, Journal of Clinical Investigation, volume 72, pages 122-127 (1983)).
Agents claimed for increasing ocular mucin and/or tear production include vasoactive intestinal polypeptide (Dartt et. al., Vasoactive intestinal peptide-stimulated glycocongjugate secretion from conjunctival goblet cells, Experimental Eye Research, volume 63, pages 27-34, (1996)), gefarnate (Nakmura et. al., Gefarnate stimulates secretion of mucin-like glycoproteins by corneal epithelium in vitro and protects corneal epithelium from dessication in vivo, Experimental Eye Research, volume 65, pages 569-574 (1997)), liposomes (U.S. Pat. No. 4,818,537), androgens (U.S. Pat. No. 5,620,921), melanocycte stimulating hormones (U.S. Pat. No. 4,868,154), phosphodiesterase inhibitors (U.S. Pat. No. 4,753,945), and retinoids (U.S. Pat. No. 5,455,265). However, many of these compounds or treatments suffer from a lack of specificity, efficacy and potency and none of these agents have been marketed so far as therapeutically useful products to treat dry eye and related ocular surface diseases.
U.S. Pat. No. 5,696,166 (Yanni et al.) discloses compositions containing naturally occurring HETEs, or derivatives thereof, and methods of use for treating dry eye. Yanni et al. discovered that compositions comprising HETEs increase ocular mucin secretion when administered to a patient and are thus useful in treating dry eye.
Metabolism of compounds biosynthesized from arachidonic acid, such as prostaglandins and certain HETEs, are known to produce modifications such as oxidation of the hydroxyl group at carbon 15 (prostaglandin and HETE numbering) to a ketone, saturation of the 13,14-olefin, hydroxylation of carbon 20, and xcex2-oxidation of the carboxylic acid chain to a new carboxylic acid with two fewer carbons (Granstom, E.; Kumlin, M. Metabolism of prostaglandins and lipoxygenase a products: relevance for eicosanoid bioassay. In Prostaglandins and Related Substances, a Practical Approach; Bennedetto, C., McDonald-Gibson, R. G., Nigam, S., and Slater, T. F., Eds.; IRL Press: Oxford, UK, 1987; Chapter 2, pp. 5-27). The compounds of formulas (II-VI) have been reported in the literature or are commercially available: (1) Formula (II): Haviv et al., J. Med. Chem., volume 30, pages 254-263 (1987); (2) Formula (III): Van Wauwe et al., Eicosanoids, volume 5, pages 141-146 (1992); (3) Formula (IV): Lumin et al., J. Chem. Soc., Chem. Commun., volume 5, pages 389-390 (1987); and (4) Formula (V): Hadjiagapiou et al., J. Biol. Chem., volume 265, pages 4369 4373 (1990); and Formula (VI): commercially available from Cayman Chemical Co., Sigma Chemical Co., and Biomol Inc. 
To the best of our knowledge, however, none of these compounds has been associated with the treatment of dry eye.
In view of the foregoing, there is a need for an effective, convenient treatment for dry eye that is capable of alleviating symptoms, as well as treating the underlying physical and physiological deficiencies of dry eye.
The present invention is directed to compounds, compositions and methods of use. The present invention is particularly directed to compositions and methods for the treatment of dry eye and other disorders requiring the wetting of the eye, including symptoms of dry eye associated with refractive surgery such as LASIK surgery. More specifically, the present invention discloses (5Z,8Z,11Z,13E)-15-hydroxyeicosa-5,8,11,13-tetraenoic acid (15-HETE)-related molecules, compositions and methods of use. The compositions are preferably administered topically to the eye.
The present invention is directed to metabolites of 15-HETE derivatives, compositions and methods of use. It is believed that, among other utilities, the compounds stimulate ocular mucin production and/or secretion following topical ocular application and are therefore believed to be useful in treating dry eye. These compounds are of formula I: 
wherein:
R1 is CO2R, CONR2R3, CH2OR4, CH2NR5R6, CH2N3, CH2Hal, CH2NO2, CH2SR20, COSR21 or 2,3,4,5-tetrazol-1-yl, wherein:
R is H or CO2R forms a pharmaceutically acceptable salt or a pharmaceutically acceptable ester;
NR2R3 and NR5R6 are the same or different and comprise a free or functionally modified amino group, e.g., R2, R3, R5 and R6 are the same o r different and are H, alkyl, cycloalkyl, aralkyl, aryl, OH, or alkoxy, with the proviso that at most only one of R2 and R3 are OH or alkoxy and at most only one of R5 and R6 are OH or alkoxy;
OR4 comprises a free or functionally modified hydroxy group, e.g., R4 is H, acyl; alkyl, cycloalkyl, aralkyl or aryl;
Hal is F, Cl, Br or I;
SR20 comprises a free or functionally modified thiol group;
R21 is H or COSR21 forms a pharmaceutically acceptable salt or a pharmaceutically acceptable thioester;
E-D is CH2CH2CH2 or cis-CH2CHxe2x95x90CH; or E is trans-CHxe2x95x90CH and D is CH(OH) in either configuration, wherein the OH is free or functionally modified; or E is CH2CH2 and D is a direct bond;
p is 1 or 3 when E-D is CH2CH2CH2 or cis-CH2CHxe2x95x90CH, or when E is trans-CHxe2x95x90CH and D is CH(OH) in either configuration, wherein the OH is free or functionally modified; or p is 0 when E is CH2CH2 and D is a direct bond;
G-T is CH2CH2, CH(SR7)CH2 or trans-CHxe2x95x90CH;
R7 is H, alkyl, aryl, aralkyl, cycloalkyl or acyl;
Y is CH(OH) in either configuration, in which the OH is free of functionally modified, or Cxe2x95x90O (i.e., a carbonyl group);
n is 0, 2 or 4; and
Z is CH3, CO2R, CONR2R3 or CH2OR4; with the proviso that compounds comprising all of the following substituents are excluded from the methods of treating dry eye-type diseases and disorders, compositions and composition of matter (i.e., compounds per se) claims herein:
R1 is CO2R or CONHR2; E-D is cis-CH2CHxe2x95x90CH; p is 3; G-T is trans-CHxe2x95x90CH; Y is CH(OH) in either configuration, wherein the OH group is free or is acylated to form OC(O)R, wherein R is H, substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, or arylalkyl, wherein the substitutent is made with a moiety selected from the group consisting of: alkyl, halogen, and free or functionally modified hydroxy; and Z is CH3;
and with the further proviso that the following compounds are excluded from the composition of matter (i.e., compounds per se) claims herein: 
The compounds of formula (I) may also be incorporated into phospholipids as glyceryl esters or sphingomyelin amides. Phospholipid sphingomyelin amides of the compounds of formula (I) will typically comprise a formula (I) compound amidated via its carbon 1 carboxylate to the amino group of the sphingomyelin backbone. The phospholipid formula (I) esters will comprise various phospholipids. Phospholipid esters of the compounds of formula (I) will typically comprise a formula (I) compound esterified via its carbon 1 carboxylate to the sn-1 or sn-2 position alcohol, or both, of the glycerol backbone of the phospholipid. If the sn-1 or sn-2 position of the glyceryl ester class does not contain an ester of a compound of formula (I), then such carbon positions of the glycerol backbone will comprise a methylene, ether or ester moiety linked to a substituted or unsubstituted C12-30 alkyl or alkenyl (the alkenyl group containing one or more double bonds); alkyl(cycloalkyl)alkyl; alkyl(cycloalkyl); alkyl(heteroaryl); alkyl(heteroaryl)alkyl; or alkyl-M-Q; wherein the substitution is alkyl, halo, hydroxy, or functionally modified hydroxy; M is O or S; and Q is H, alkyl, alkyl(cycloalkyl)alkyl, alkyl(cycloalkyl), alkyl(heteroaryl) or alkyl(heteroaryl)alkyl. However, at least one of the sn-1 or sn-2 position alcohols of the glycerol backbone must form an ester with a compound of formula (I) via the carbon 1 carboxylate of the latter. Preferred phospholipid-formula (I) esters will be of the phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine, and phospatidylinositol type. The most preferred phospholipid-formula (I) esters will comprise a formula (I) compound esterified via its carbon 1 carboxylate to the alcohol at the sn-2 position of phosphatidylcholine, phosphatidylethanolamine or phosphatidylinositol. The phospholipid-formula (I) esters and sphingomyelin amides may be synthesized using various phospholipid synthetic methods known in the art; see for example, Tsai et al., Biochemistry, volume 27, page 4619 (1988); and Dennis et al., Biochemistry, volume 32, page 10185 (1993).
Included within the scope of the present invention are the individual enantiomers of the compounds of the present invention, as well as their racemic and non-racemic mixtures. The individual enantiomers can be enantioselectively synthesized from the appropriate enantiomerically pure or enriched starting material by means such as those described below. Alternatively, they may be enantioselectively synthesized from racemic/non-racemic or achiral starting materials. (Asymmetric Synthesis; J. D. Morrison and J. W. Scott, Eds.; Academic Press Publishers: New York, 1983-1985, volumes 1-5; Principles of Asymmetric Synthesis; R. E. Gawley and J. Aube, Eds.; Elsevier Publishers: Amsterdam, 1996). They may also be isolated from racemic and non-racemic mixtures by a number of known methods, e.g. by purification of a sample by chiral HPLC (A Practical Guide to Chiral Separations by HPLC; G. Subramanian, Ed.; VCH Publishers: New York, 1994; Chiral Separations by HPLC; A.M. Krstulovic, Ed.; Ellis Horwood Ltd. Publishers, 1989), or by enantioselective hydrolysis of a carboxylic acid ester sample by an enzyme (Ohno, M.; Otsuka, M. Organic Reactions, volume 37, page 1 (1989)). Those skilled in the art will appreciate that racemic and non-racemic mixtures may be obtained by several means, including without limitation, nonenantioselective synthesis, partial resolution, or even mixing samples having different enantiomeric ratios. Departures may be made from such details within the scope of the accompanying claims without departing from the principles of the invention and without sacrificing its advantages. Also included within the scope of the present invention are the individual isomers substantially free of their respective enantiomers.
As used herein, the terms xe2x80x9cpharmaceutically acceptable saltxe2x80x9d, xe2x80x9cpharmaceutically acceptable esterxe2x80x9d and pharmaceutically acceptable thioesterxe2x80x9d means any salt, ester or thioester, respectively, that would be suitable for therapeutic administration to a patient by any conventional means without significant deleterious health consequences; and xe2x80x9cophthalmically acceptable saltxe2x80x9d, xe2x80x9cophthalmically acceptable esterxe2x80x9d and xe2x80x9cophthalmically acceptable thioesterxe2x80x9d means any pharmaceutically acceptable salt, ester or thioester, respectively, that would be suitable for ophthalmic application, i.e. non-toxic and non-irritating.
The term xe2x80x9cfree hydroxy groupxe2x80x9d means an OH. The term xe2x80x9cfunctionally modified hydroxy groupxe2x80x9d means an OH which has been functionalized to form: an ether, in which an alkyl, aryl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, or heteroaryl group is substituted for the hydrogen; an ester, in which an acyl group is substituted for the hydrogen; a carbamate, in which an aminocarbonyl group is substituted for the hydrogen; or a carbonate, in which an aryloxy-, heteroaryloxy-, alkoxy-, cycloalkoxy-, heterocycloalkoxy-, alkenyloxy-, cycloalkenyloxy-, heterocycloalkenyloxy-, or alkynyloxy-carbonyl group is substituted for the hydrogen. Preferred moieties include OH, OCH2C(O)CH3,OCH2C(O)C2H5, OCH3, OCH2CH3, OC(O)CH3, and OC(O)C2H5.
The term xe2x80x9cfree amino groupxe2x80x9d means an NH2. The term xe2x80x9cfunctionally modified amino groupxe2x80x9d means an NH2 which has been functionalized to form: an aryloxy-, heteroaryloxy-, alkoxy-, cycloalkoxy-, heterocycloalkoxy-, alkenyl-, cycloalkenyl-, heterocycloalkenyl-, alkynyl-, or hydroxy-amino group, wherein the appropriate group is substituted for one of the hydrogens; an aryl-, heteroaryl-, alkyl-, cycloalkyl-, heterocycloalkyl-, alkenyl-, cycloalkenyl-, heterocycloalkenyl-, or alkynyl-amino group, wherein the appropriate group is substituted for one or both of the hydrogens; an amide, in which an acyl group is substituted for one of the hydrogens; a carbamate, in which an aryloxy-, heteroaryloxy-, alkoxy-, cycloalkoxy-, heterocycloalkoxy-, alkenyl-, cycloalkenyl-, heterocycloalkenyl-, or alkynyl-carbonyl group is substituted for one of the hydrogens; or a urea, in which an aminocarbonyl group is substituted for one of the hydrogens. Combinations of these substitution patterns, for example an NH2 in which one of the hydrogens is replaced by an alkyl group and the other hydrogen is replaced by an alkoxycarbonyl group, also fall under the definition of a functionally modified amino group and are included within the scope of the present invention. Preferred moieties include NH2, NHCH3, NHC2H5, N(CH3)2, NHC(O)CH3, NHOH, and NH(OCH3).
The term xe2x80x9cfree thiol groupxe2x80x9d means an SH. The term xe2x80x9cfunctionally modified thiol groupxe2x80x9d means an SH which has been functionalized to form: a thioether, where an alkyl, aryl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, alkynyl, or heteroaryl group is substituted for the hydrogen; or a thioester, in which an acyl group is substituted for the hydrogen. Preferred moieties include SH, SC(O)CH3, SCH3, SC2H5, SCH2C(O)C2H5, and SCH2C(O)CH3.
The term xe2x80x9cacylxe2x80x9d represents a group that is linked by a carbon atom that has a double bond to an oxygen atom and a single bond to another carbon atom.
The term xe2x80x9calkylxe2x80x9d includes straight or branched chain aliphatic hydrocarbon groups that are saturated and have 1 to 15 carbon atoms. The alkyl groups may be interrupted by one or more heteroatoms, such as oxygen, nitrogen, or sulfur, and may be substituted with other groups, such as halogen, hydroxyl, aryl, cycloalkyl, aryloxy, or alkoxy. Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and t-butyl.
The term xe2x80x9ccycloalkylxe2x80x9d includes straight or branched chain, saturated or unsaturated aliphatic hydrocarbon groups which connect to form one or more rings, which can be fused or isolated. The rings may be substituted with other groups, such as halogen, hydroxyl, aryl, aryloxy, alkoxy, or lower alkyl. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term xe2x80x9cheterocycloalkylxe2x80x9d refers to cycloalkyl rings that contain at least one heteroatom such as O, S, or N in the ring, and can be fused or isolated. The rings may be substituted with other groups, such as halogen, hydroxyl, aryl, aryloxy, alkoxy, or lower alkyl. Preferred heterocycloalkyl groups include pyrrolidinyl, tetrahydrofuranyl, piperazinyl, and tetrahydropyranyl.
The term xe2x80x9calkenylxe2x80x9d includes straight or branched chain hydrocarbon groups having 1 to 15 carbon atoms with at least one carbon-carbon double bond, the chain being optionally interrupted by one or more heteroatoms. The chain hydrogens may be substituted with other groups, such as halogen. Preferred straight or branched alkenyl groups include, allyl, 1-butenyl, 1-methyl-2-propenyl and 4-pentenyl.
The term xe2x80x9ccycloalkenylxe2x80x9d includes straight or branched chain, saturated or unsaturated aliphatic hydrocarbon groups which connect to form one or more non-aromatic rings containing a carbon-carbon double bond, which can be fused or isolated. The rings may be substituted with other groups, such as halogen, hydroxyl, alkoxy, or lower alkyl. Preferred cycloalkenyl groups include cyclopentenyl and cyclohexenyl.
The term xe2x80x9cheterocycloalkenylxe2x80x9d refers to cycloalkenyl rings which contain one or more heteroatoms such as 0, N, or S in the ring, and can be fused or isolated. The rings may be substituted with other groups, such as halogen, hydroxyl, aryl, aryloxy, alkoxy, or lower alkyl. Preferred heterocycloalkenyl groups include pyrrolidinyl, dihydropyranyl, and dihydroflranyl.
The term xe2x80x9ccarbonyl groupxe2x80x9d represents a carbon atom double bonded to an oxygen atom, wherein the carbon atom has two free valencies.
The term xe2x80x9caminocarbonylxe2x80x9d represents a free or functionally modified amino group bonded from its nitrogen atom to the carbon atom of a carbonyl group, the carbonyl group itself being bonded to another atom through its carbon atom.
The term xe2x80x9clower alkylxe2x80x9d represents alkyl groups containing one to six carbons (C1-C6).
The term xe2x80x9chalogenxe2x80x9d represents fluoro, chloro, bromo, or iodo.
The term xe2x80x9carylxe2x80x9d refers to carbon-based rings which are aromatic. The rings may be isolated, such as phenyl, or fused, such as naphthyl. The ring hydrogens may be substituted with other groups, such as lower alkyl, halogen, free or functionalized hydroxy, trihalomethyl, etc. Preferred aryl groups include phenyl, 3-(trifluoromethyl)phenyl, 3-chlorophenyl, and 4-fluorophenyl.
The term xe2x80x9cheteroarylxe2x80x9d refers to aromatic hydrocarbon rings which contain at least one heteroatom such as O, S, or N in the ring. Heteroaryl rings may be isolated, with 5 to 6 ring atoms, or fused, with 8 to 10 atoms. The heteroaryl ring(s) hydrogens or heteroatoms with open valency may be substituted with other groups, such as lower alkyl or halogen. Examples of heteroaryl groups include imidazole, pyridine, indole, quinoline, furan, thiophene, pyrrole, tetrahydroquinoline, dihydrobenzofuran, and dihydrobenzindole.
The terms xe2x80x9caryloxyxe2x80x9d, xe2x80x9cheteroaryloxyxe2x80x9d, xe2x80x9calkoxyxe2x80x9d, xe2x80x9ccycloalkoxyxe2x80x9d, xe2x80x9cheterocycloalkoxyxe2x80x9d, xe2x80x9calkenyloxyxe2x80x9d, xe2x80x9ccycloalkenyloxyxe2x80x9d, xe2x80x9cheterocycloalkenyloxyxe2x80x9d, and xe2x80x9calkynyloxyxe2x80x9d represent an aryl, heteroaryl, alkyl, cycloalkyl, heterocycloalkyl, alkenyl, cycloalkenyl, heterocycloalkenyl, or alkynyl group, respectively, attached through an oxygen linkage.
The terms xe2x80x9calkoxycarbonylxe2x80x9d, xe2x80x9caryloxycarbonylxe2x80x9d, xe2x80x9cheteroaryloxycarbonylxe2x80x9d, xe2x80x9ccycloalkoxycarbonylxe2x80x9d, xe2x80x9cheterocycloalkoxycarbonylxe2x80x9d, xe2x80x9calkenyloxycarbonylxe2x80x9d, xe2x80x9ccycloalkenyloxycarbonylxe2x80x9d, xe2x80x9cheterocycloalkenyloxycarbonylxe2x80x9d, and xe2x80x9calkynyloxycarbonylxe2x80x9d represent an alkoxy, aryloxy, heteroaryloxy, cycloalkoxy, heterocycloalkoxy, alkenyloxy, cycloalkenyloxy, heterocycloalkenyloxy, or alkynyloxy group, respectively, bonded from its oxygen atom to the carbon of a carbonyl group, the carbonyl group itself being bonded to another atom through its carbon atom.
Preferred compounds of the present invention are those wherein:
R1 is CO2R, wherein R is H, or CO2R forms an ophthalmically acceptable salt or an ophthalmically acceptable ester;
n is 4; and
Z is CH3, CH2OH, or CO2R, wherein R is H, or CO2R forms an ophthalmically acceptable salt or an ophthalmically acceptable ester.
The following compounds 1-6 are particularly preferred compounds of the present invention: 
Salt forms of the formula (I) compounds are preferred as it is believed that the neat salts are more stable than the corresponding neat acids. Preferred salts of the present invention are those wherein a terminal carboxylate of formula (I) (i.e., wherein R1 is CO2R) forms a salt with cations selected from: Na+, K+, NH4+, benzyltrimethylammonium ion, tetrabutylammonium ion, and phenyltrimethyl ammonium ion.
As used hereinafter, the term xe2x80x9ccompounds of formula (I),xe2x80x9d refers to compounds of formula (I), and/or the phospholipid-formula (I) esters or amides described above. The compositions of the present invention comprise one or more compounds of formula (I) and a pharmaceutically acceptable carrier. The compositions are formulated in accordance with methods known in the art for the particular route of administration desired for the prevention, treatment or amelioration of the particular disease or disorder targeted. The level of peroxy compounds in the HETE derivative raw materials that are used to prepare the pharmaceutical formulations of the present invention may have an impact on the HETE derivative""s biological activity. Although the precise relationship has not been defined, it is preferable to use HETE derivative raw material supplies containing peroxy compounds at levels no greater than about 0.3 ppm. Methods for determining peroxy levels are known in the art (e.g., European Pharmacopoeia 1997 3rd Ed., Method 2.5.5-Peroxide Value).
As used herein, the term xe2x80x9cpharmaceutically acceptable carrierxe2x80x9d refers to any formulation which is safe, and provides the appropriate delivery of an effective amount of one or more compounds of formula (I) for the prevention, treatment or amelioration of the disease or disorder targeted.
As used herein, the term xe2x80x9cpharmaceutically effective amountxe2x80x9d refers to an amount of one or more compounds of formula (I) that, when administered to a patient, prevents, treats or ameliorates a disease or disorder, or conditions associated thereof As used herein, xe2x80x9can ophthalmically effective amountxe2x80x9d refers to an amount of one or more compounds of formula (I) that, when administered to a patient, prevents, treats or ameliorates an ophthalmic disease or disorder, or conditions associated thereof. For the treatment of dry eye, such an effective amount will stimulate secretion of mucin in the eye and thus eliminate or improve dry eye conditions when administered to the eye. As used herein, xe2x80x9can effective amount to treat dry eyexe2x80x9d refers to an amount of one or more compounds of formula (I) that, when administered to a patient, prevents, treats or ameliorates a dry eye disease or disorder, or conditions associated thereof. Generally, the compounds of formula (I) will be contained in a composition of the present invention in a concentration range of about 0.00001 to 10 per cent weight/volume (xe2x80x9c% w/vxe2x80x9d). Preferred ophthalmic, including dry eye-treatment, compositions will contain one or more compounds of formula (I) in a concentration of from about 0.00001-0.01% w/v.
The present invention is particularly directed to compositions useful in treating dry eye. Preferably, such compositions will be formulated as solutions, suspensions and other dosage forms for topical administration. Aqueous solutions are generally preferred, based on ease of formulation, biological compatibility (especially in view of the malady to be treated, e.g., dry eye-type diseases and disorders), as well as a patient""s ability to easily administer such compositions by means of instilling one to two drops of the solutions in the affected eyes. However, the compositions may also be suspensions, viscous or semi-viscous gels, or other types of solid or semi-solid compositions. Suspensions may be preferred for compounds of formula (I) which are less soluble in water.
Preferably, the ophthalmic compositions of the present invention will also contain ethanol. As used herein, xe2x80x9can effective concentration of ethanolxe2x80x9d refers to a concentration that enhances the biological efficacy of the formula (I) compositions in vivo. In general, the concentration of ethanol necessary for the enhancement of the compounds of formula (I) is believed to be somewhat proportional to the concentration of the formula (I) compound(s) administered. If a relatively high concentration of formula (I) compound(s), e.g., above 0.01% w/v, is administered, the concentration of ethanol in such compositions may be proportionally less than analogous compositions containing lower concentrations of formula (I) compounds. In general, however, the ethanol concentration contained in the ophthalmic compositions of the present invention will range from about 0.001-2% w/v. Compositions containing formula (I) concentrations of about 0.00001-0.02% w/v preferably will contain ethanol in a concentration of about 0.005-0.2% w/v, and most preferably, about 0.02-0.10% w/v.
Preferably, the compositions of the present invention will also contain a surfactant. Various surfactants useful in topical ophthalmic formulations may be employed. The surfactant(s) may provide additional chemical stabilization of the formula (I) compounds and may further provide for the physical stability of the compounds. In other words, the surfactants may aid in preventing chemical degradation of the compounds of formula (I) and also prevent the compounds from binding to the containers in which their compositions are packaged. As used herein, xe2x80x9can effective concentration of surfactant(s)xe2x80x9d refers to a concentration that enhances the chemical and physical stability of formula (I) compound(s). Examples of surfactants include, but are not limited to: Cremophore(copyright) EL, polyoxyl 20 ceto stearyl ether, polyoxyl 40 hydrogenated castor oil, polyoxyl 23 lauryl ether and poloxamer 407 may be used in the compositions. A preferred surfactant is polyoxyl 40 stearate. The concentration of surfactant will vary, depending on the concentration of formula (I) compound(s) and optional ethanol present in the formulation. In general, however, the surfactant(s) concentration will be about 0.001 to 2.0% w/v. Preferred compositions of the present invention will contain about 0.1% w/v of polyoxyl 40 stearate.
The compositions of the present invention may also include various other ingredients, such as tonicity agents, buffers, preservatives, co-solvents and viscosity building agents.
Various tonicity agents may be employed to adjust the tonicity of the composition, preferably to that of natural tears for ophthalmic compositions. For example, sodium chloride, potassium chloride, magnesium chloride, calcium chloride, dextrose and/or mannitol may be added to the composition to approximate physiological tonicity. Such an amount of tonicity agent will vary, depending on the particular agent to be added. In general, however, the compositions will have a tonicity agent concentration of about 0.1-1.5% w/v. Sodium chloride in the amount of 0.75% w/v is preferred.
An appropriate buffer system (e.g., sodium phosphate, sodium acetate, sodium citrate, sodium borate or boric acid) may be added to the compositions to prevent pH drift under storage conditions. The particular concentration will vary, depending on the agent employed. In general, however, such a concentration will range from about 0.02 to 2.0% w/v. Preferred compositions will contain about 0.25% w/v of boric acid.
Antioxidants may be added to compositions of the present invention to protect the formula (I) compounds from oxidation during storage. Examples of such antioxidants include, but are not limited to, vitamin E and analogs thereof, ascorbic acid and derivatives, and butylated hydroxyanisole (BHA).
Compositions formulated for the treatment of dry eye-type diseases and disorders may also comprise aqueous carriers designed to provide immediate, short-term relief of dry eye-type conditions. Such carriers can be formulated as a phospholipid carrier or an artificial tears carrier, or mixtures of both. As used in this paragraph and the immediately succeeding paragraph, the term xe2x80x9cphospholipidxe2x80x9d refers only to the phospholipids of the phospholipid carrier, does not refer to a compound of formula (I) and, as such, does not contain a formula (I) compound. As used herein, xe2x80x9cphospholipid carrierxe2x80x9d and xe2x80x9cartificial tears carrierxe2x80x9d refer to aqueous compositions which: (i) comprise one or more phospholipids (in the case of phospholipid carriers) or other compounds, which lubricate, xe2x80x9cwet,xe2x80x9d approximate the consistency of endogenous tears, aid in natural tear build-up, or otherwise provide temporary relief of dry eye symptoms and conditions upon ocular administration; (ii) are safe; and (iii) provide the appropriate delivery vehicle for the topical administration of an effective amount of one or more compounds of formula (I). Examples or artificial tears compositions useful as artificial tears carriers include, but are not limited to, commercial products, such as Tears Natural(copyright), Tears Naturale II(copyright), Tears Naturale Free(copyright), and Bion Tears(copyright) (Alcon Laboratories, Inc., Fort Worth, Tex.). Examples of phospholipid carrier formulations include those disclosed in U.S. Pat. No. 4,804,539 (Guo et al.), U.S. Pat. No. 4,883,658 (Holly), U.S. Pat. No. 4,914,088 (Glonek), U.S. Pat. No. 5,075,104 (Gressel et al.), U.S. Pat. No. 5,278,151 (Korb et al.), U.S. Pat. No. 5,294,607 (Glonek et al.), U.S. Pat. No. 5,371,108 (Korb et al.), U.S. Pat. No. 5,578,586 (Glonek et al.); the foregoing patents are incorporated herein by reference to the extent they disclose phospholipid compositions useful as phospholipid carriers of the present invention.
The phospholipids useful in the phospholipid carriers are any natural or synthetic phospholipid compound comprising a glycerol-phosphoric acid ester or sphingomyelin backbone. Examples of phospholipids useful in the present invention include those of formula (VI): 
wherein, X21 and X22 are the same or different and are O, NH(Cxe2x95x90O), O(Cxe2x95x90O), or a direct bond;
R22 is H or CHxe2x95x90CH(CH2)12CH3;
X21xe2x80x94R1 is OH, or R1 is C12-26 substituted or unsubstituted alkyl or alkenyl;
R2 is C12-26 substituted or unsubstituted alkyl or alkenyl; and
R3 is H, OH, OCH2CH(NH3+)COOxe2x88x92, OCH2CH2NH3+, OCH2CH2N+(CH3)3, OCH2CH(OH)CH2OH and O-inositol.
The phospholipids may be present as racemic or non-racemic compounds. Preferred phospholipids are those wherein X21xe2x80x94Ri and/or X22xe2x80x94R2 comprise fatty acid esters or amides. Natural fatty acids are saturated, monounsaturated or polyunsaturated. Examples of fatty acid residues include, but are not limited to, laurate, myristate, palmitate, palmitoleate, stearate, oleate, linoleate, linolenate, eicosanoate, docosanoate and lignocerate. Preferred phospholipid types are the phosphatidylethanolamines, phosphatidylcholines, phosphatidylserines, phospatidylinositols and sphingomyelins. Examples of specific phospholipids include: 1,2-dipalmitoyl phosphatidyl choline (xe2x80x9cDPPCxe2x80x9d) 1,2-dipalmityl phosphatidyl glycerol (xe2x80x9cDPPGxe2x80x9d), N-stearyl sphingomyelin, N-palmityl sphingomyelin, N-oleyl sphingomyelin, 1,2-distearoyl phosphatidyl ethanolamine (xe2x80x9cDSPExe2x80x9d), 1,2-distearoyl phosphatidyl inositol (xe2x80x9cDSPIxe2x80x9d), 1-stearoyl-2-palmitoyl phosphatidyl ethanolamine (xe2x80x9cSPPExe2x80x9d), 1-stearoyl-2-palmitoyl phosphatidyl choline (xe2x80x9cSPPCxe2x80x9d), 1,2-dipalmitoyl phosphatidyl ethanolamine (xe2x80x9cDPPExe2x80x9d), 1,2-dioleoyl phophatidyl ethanolamine (xe2x80x9cDOPExe2x80x9d), 1,2-dioleoyl phophatidyl serine (xe2x80x9cDOPSxe2x80x9d), and 1,2-dipalmitoyl phosphatidyl serine (xe2x80x9cDPPSxe2x80x9d). The most preferred phospholipid carriers are the phosphatidylethanolamines and sphingomyelins. Phospholipids are available from a variety of natural sources and may be synthesized by methods known in the art; see, for example, Tsai et al., Biochemistry, volume 27, page 4619 (1988); and Dennis et. al., Biochemistry, volume 32, page 10185 (1993).
Other compounds designed to lubricate, xe2x80x9cwet,xe2x80x9d approximate the consistency of endogenous tears, aid in natural tear build-up, or otherwise provide temporary relief of dry eye symptoms and conditions upon ocular administration the eye are known in the art. Such compounds may enhance the viscosity of the composition, and include, but are not limited to: monomeric polyols, such as, glycerol, propylene glycol, ethylene glycol; polymeric polyols, such as, polyethylene glycol, hydroxypropylmethyl cellulose (xe2x80x9cHPMCxe2x80x9d), carboxy methylcellulose sodium, hydroxy propylcellulose (xe2x80x9cHPCxe2x80x9d), dextrans, such as, dextran 70; water soluble proteins, such as gelatin; and vinyl polymers, such as, polyvinyl alcohol, polyvinylpyrrolidone, povidone and carbomers, such as, carbomer 934P, carbomer 941, carbomer 940, carbomer 974P.
Other compounds may also be added to the ophthalmic compositions of the present invention to increase the viscosity of the carrier. Examples of viscosity enhancing agents include, but are not limited to: polysaccharides, such as hyaluronic acid and its salts, chondroitin sulfate and its salts, dextrans, various polymers of the cellulose family; vinyl polymers; and acrylic acid polymers. In general, the phospholipid carrier or artificial tears carrier compositions will exhibit a viscosity of 1 to 400 centipoises (xe2x80x9ccpsxe2x80x9d). Preferred compositions containing artificial tears or phospholipid carriers will exhibit a viscosity of about 25 cps.
Topical ophthalmic products are typically packaged in multidose form. Preservatives are thus required to prevent microbial contamination during use. Suitable preservatives include: benzalkonium chloride, chlorobutanol, benzododecinium bromide, methyl paraben, propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, polyquaternium-1, or other agents known to those skilled in the art. Such preservatives are typically employed at a level of from 0.001 to 1.0% w/v. Unit dose compositions of the present invention will be sterile, but typically unpreserved. Such compositions, therefore, generally will not contain preservatives.
The preferred compositions of the present invention are intended for administration to a human patient suffering from dry eye or symptoms of dry eye. Preferably, such compositions will be administered topically. In general, the doses used for the above described purposes will vary, but will be in an effective amount to increase mucin production in the eye and thus eliminate or improve dry eye conditions. Generally, 1-2 drops of such compositions will be administered 1-10 times per day for the treatment of dry eye or other ocular disease or disorder. Preferably, 1-2 drops of the compositions will be administered 1-4 times per day.
The present invention is also directed to stable, stock compositions comprising one or more compounds of formula (I, and ethanol. The inventors believe that storing the compounds of formula (I) in an ethanolic solution provides greater stability of the compounds of formula (I) over analogous aqueous compositions, or neat compounds of formula (I) compositions. Such compositions comprise one or more compounds of formula (I) and an amount of ethanol to solubilize the compounds of formula (I) in solution. Preferably, the ethanolic stock solutions will contain anhydrous ethanol, but aqueous ethanolic solutions are also contemplated by the present invention. Generally, the stock solutions will contain ethanol in a concentration of about 25 to 100% volume/volume (xe2x80x9cv/vxe2x80x9d). Typically, such stock solutions will contain compounds of formula (I) in high concentration relative to the pharmaceutical compositions of the present invention.